There have been a number of proposed links between the immune system and the nervous system (and possible interactions with the reproductive system) including: 1) prolonged post-natal development/maturation of both systems. 2) infection in the pregnant mother and possible transfer of factors of the pro-inflammatory cascade (TNFalpha, Interleukin-6) to the offspring and long-term effects on the child as related to an immune-mediated response. 3) transfer of active virsus into the brain (e.g., Herpes, HIV, West-Nile) and the manifestation of cognitive deficits/dementia. 4) increase of cognitive deficits in human cases related to autoimmune disease (e.g., AIDs, Multiple Sclerosis, Tryptophan-induced autoimmunity), 5) the lack of success with therapeutic intervention with anti-inflammatory agents for cognitive impairment suggesting a more complicated interactions between the systems than previously anticipated. Local activation of inflammatory cells in the brain may contribute to neuronal death that occurs following acute brain injury as well as more progressive degenerative processes. In this network, various cells communicate and regulate complex processes of initiation, propagation, and suppression of immune and inflammatory responses. Through the resident immune cell network and the cell-cell interactions between the neurons and glia, a cascade of responses occur upon insult that signal events that may lead to neuronal death. The inflammatory response in the brain serves much the same was as that in the periphery. As a host defense response it serves to protect the brain however, when the response becomes dysregulated this can lead to adverse events. Under this framework we have reported that microglia cells are critical not only in the initial phase of the damage response but also in the repair process following injury. The purpose of this project is to identify the critical features of the glia response that may either cause or exacerbate an ongoing process of neuronal death and how these features change with chemical exposure, immune system integrity, and life stage. These features include not only the individual cell response but also the extracellular environment that may influence the outcome of such responses. Within the framework of exposure to environmental agents, there exists a substantial database to suggest that acute responses of the immune system can occur as a result of chemical exposure. Quite often, the agents or factors that have the capacity to alter the immune system are shown to also alter the nervous system. Thus, it is the purpose of this project to attempt to identify interactions between the two systems that may contribute not only to acute adverse effects but also to long-term adverse outcomes. Understanding the link between the resident immune cells of the brain, the systemic immune system, manifestation of neurodegenerative disease, and the ability/inability to mount a regenerative response will provide a critical step toward identifying approaches to treat such conditions.